Two genes, PS-1 and PS-2, have been identified as causal in the development of familial forms of Alzheimer's disease. Recent evidence has suggested that both PS-1 and PS-2 may exert their effects, at least partially, through direct or indirect effects on endogenous cell death pathways. For example, PS-1 deficient lines of mice die at birth and massive death of neuronal progenitor cells is observed in these animals (Shen et al., 1997). These data suggest that normal PS-1 expression may protect cells from apoptosis while lack of expression or mutant alleles of PS-1 may sensitize cells to apoptosis. In contrast, PS-2 has been reported to induce apoptosis. This was suggested by data demonstrating a dominant negative form of PS-2 protects T cells from T cell receptor mediated apoptosis (Vito et al., 1996). Furthermore, expression of PS-2 sensitizes cells to apoptosis and expression of a mutant allele of PS-2 directly induces apoptosis in PC12 cells (Wolozin et al., 1996). Taken together, these data provide strong evidence that PS-1 and PS-2 may directly effect the ability of a cell to undergo apoptosis. This proposal tests the hypothesis that PS-1 and PS-2 mediate apoptosis in T cells and further proposes experiments to determine the mechanism by which these proteins mediate their effects. Recently, we have made the novel observation that cell death in T cells may be prevented by the expression of Notch. Since PS-1 is thought to regulate Notch expression, we will determine if Notch plays a role in cell death pathways modulated by PS-1 and PS-2. The results from these experiments will provide important clues into the function of the these proteins in T cells and PC12 cells and will provide a basis for further experimentation of the role of these proteins in apoptosis.